Most therapeutic compounds are delivered to the target organ or tissue through the circulation. However, in most cases the drug or other treatment will not only target the diseased organ or tissues, but will also be taken up by other organs and tissues in the body. This can result in undesirable side effects due to, for example, generalized toxic effects throughout the patient's body. Thus, it would be desirable to selectively target specific organs or tissues, or specific types of tumor cells. In addition, coupling of a therapeutic compound to a targeting molecule can improve the uptake properties of the compound into the targeted tissue or cells, resulting in a more effective molecule. Therefore, coupling to targeting molecules yields compounds that are more effective and less toxic than the parental compound, see Curnis et al., 2000, Nature Biotechnol. 18, 1185-1190. This can be applied to a wide range of compounds, such as peptides, proteins, cytostatic agents, antibiotic and antiviral agents.
In the case of neuromuscular diseases such as myotonic dystrophy (MD) or spinal muscular atrophy (SMA) transport across the blood brain barrier and uptake into the neuronal cells is mandatory for an effective therapy. Neuron-specific peptides can be conjugated to, for example, antisense oligonucleotides (AONs) and small interfering RNA (siRNA). AONs and siRNAs have high potency to be applied as new classes of medicines for treatment of specific diseases by blocking undesired gene transcription. In the field of SMA therapy antisense-induced exon inclusion is gaining attention as a novel and promising tool for correction of the translational reading frame of the SMN2 (survival of motor neuron 2) transcript. The aim is to manipulate splicing in such a manner that the targeted exon will be included (through binding of the AONs to pre-mRNA). This would allow correction of the translational reading frame, and induction of the synthesis of a full length SMN protein.
Several reports have shown the therapeutic potential of the exon inclusion strategy for restoring full length SMN protein production (Hua et al., 2007, PLoS Biol. 5, e73; Baughan et al., 2006, Mol. Ther. 14, 54-62). However, the biggest hurdle to overcome is the poor in vivo neuronal uptake of these AONs and transport across the blood brain barrier. For other neuronal diseases, or diseases of the brain (e.g. Alzheimer, Parkinson and the like) the problem is very similar, i.e. poor in vivo uptake of the therapeutic or diagnostic compounds.
In the case of neuronal or neuro-ectodermal tumors (e.g. neuroblastoma, glioblastoma and the like), targeting is also of major importance for generating an effective therapy without side effects. Chemotherapeutic drugs can act both on normal as well as cancerous tissues, leading to this targeting requirement. For anti-sense oligonucleotide (AON-) or small interfering (si)RNA-based drugs it is known that pharmacokinetic properties are unfavourable for the free drug to reach sufficient levels at the site of the tumor, because the majority is absorbed in the liver and the kidneys. The vehicle delivering the chemotherapeutic must show sufficient half life time to effectively deliver a therapeutic agent to the desired cells, also beyond the blood brain barrier.
In light of the above, it is very clear that further improvements in delivery systems are necessary to achieve specific uptake of agents such as AONs in vivo.